Synthesis and hetero-Diels-Alder reactions of (E)-α-perfluoroalkanesulfonyl-α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2006.04.156

Catalyzed by ammonium acetate, the Knoevenagel reactions of β-keto perfluoroalkanesulfones 1 with aromatic aldehydes 2 afforded α-perfluoroalkanesulfonyl-α,β-unsaturated ketones 4 in moderate to good yields. The possible mechanism for the reactions was pr

Full text of DOI:10.1016/j.tetlet.2006.04.156

Tetrahedron Letters 47 (2006) 4951–4955
Synthesis and hetero-Diels–Alder reactions of
(E)-a-perfluoroalkanesulfonyl-a,b-unsaturated ketones
Chunhui Xing,a Xianfu Li,b Shifa Zhu,a Jingwei Zhaoa and Shizheng Zhua,*
aKey Laboratory of Organofluorine Chemistry, Shanghai Institution of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin lu, Shanghai 200032, PR China
bDepartment of Chemistry, School of Science, Shanghai University, PR China
Received 17 February 2006; revised 29 April 2006; accepted 29 April 2006
Available online 26 May 2006
Abstract—Catalyzed by ammonium acetate, the Knoevenagel reactions of b-keto perfluoroalkanesulfones 1 with aromatic alde-
hydes 2 afforded a-perfluoroalkanesulfonyl-a,b-unsaturated ketones 4 in moderate to good yields. The possible mechanism for
the reactions was proposed. These fluorine-containing a,b-unsaturated ketones, which are electron-poor 1-oxa-1,3-butadienes, could
be used in inverse electron demand hetero Diels–Alder (HDA) reaction with electron-rich olefins to give tetrasubstituted dihydro-
pyrans 6 in quantitative yields.
Ó 2006 Elsevier Ltd. All rights reserved.
The sulfonyl groups are of special interest in organic
chemistry for their ambivalent nature.1–3 They may
function either as electrophiles or nucleofugic leaving
groups having an electron pair to form sulfinate anions.
Moreover, sulfonyl groups can stabilize neighboring
carbanions or activate adjacent carbon–carbon multiple
bonds for nucleophilic attack and cycloadditions due to
their strong electron-withdrawing effect.4 This capability
can be more strengthened by exchanging alkyl or aryl
substituents of sulfonyl with stronger electron-with-
drawing perfluoroalkyl group Rf.5,6
(X = CN, COOR), similar to b-keto or b-alkoxycar-
bonyl aryl sulfones ArSO2CH2COX (X = R, OR),
undergo Knoevenagel condensation reaction with
aromatic aldehydes to give 2-aryl-1-perfluoroalkane-
sulfonyl acrylonitriles or 3-aryl-2-perfluoroalkanesulfon-
yl-2-propenoates (Scheme 1).6,9
Recently, we found that the reaction of b-keto perfluo-
roalkanesulfones
RfSO2CH2COR
(Rf = ClC4F8,
R = Ph (1a) or CH3 (1b)) with aldehydes 2 was quite dif-
ferent from that of perfluoroalkanesulfonyl esters under
the traditional Knoevenagel condensation conditions,
which afforded tetrasubstituted trans-2,3-dihydrofurans
3 in good yields.10 These results could rationally explain
that the intermediate a-perfluoroalkanesulfonyl-a,b-
unsaturated ketones 4 were a better electrophilic
Michael acceptor than a-perfluoroalkanesulfonyl-a,b-
unsaturated esters. They then readily underwent
Michael addition with another molecule of 1 and were
followed by intramolecular nucleophilic displacement
to give tetrasubstituted dihydrofuran derivatives
(Scheme 2).
Just for their versatile reactivity, sulfones, called as
‘chemical chameleons’, are of great importance in
organic synthesis.1–4,7 Among their derivatives, b-keto
sulfones have gained wide applications as intermediates
in the synthesis of substituted acetylenes, olefins, allenes,
vinyl sulfones, polyfunctionalized 4H-pyrans and quino-
lines.8 Among these studies, however, less attention was
focused on the b-keto perfluoroalkanesulfones.
Several groups have reported that the perfluoro-
alkanesulfonyl acetonitriles and esters RfSO2CH2X
Knoevenagel
condensation
RfO2S
X
RfSO2CH2X + ArCHO
X=CN, COOR
Keywords: a,b-Unsaturated ketones; Knoevenagel; Ammonium acet-
ate; Hetero Diels–Alder reaction; Dihydropyran.
Ar
*
Corresponding author. Tel.: +86 21 54925185; fax: +86 21
64166128; e-mail: zhusz@mail.sioc.ac.cn
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.156

4952
C. Xing et al. / Tetrahedron Letters 47 (2006) 4951–4955
O
O
O
O
RfO2S
piperidine
(1eq)
RfO2S
R
O
R
R
RfSO2
1
+
R
R
110oC
ArCHO
Ar
SO2Rf
Ar
2
3
4
R =Ph or CH3
Rf=Cl(CF2)4
Scheme 2.
Synthesis and utilization of these active a-perflu-
oroalkanesulfonyl-a,b-unsaturated ketones are never-
theless few mentioned to date.11 Accordingly, we are
interested in their preparation and synthetic applica-
tions. As a part of further study on the chemical trans-
formations of b-keto perfluoroalkanesulfones, we now
report here the successful stereospecific synthesis of
(E)-a-perfluoroalkanesulfonyl-a,b-unsaturated ketones
4 by the Knoevenagel condensation reaction between
RfSO2CH2COR 1 and aromatic aldehydes 2 with
ammonium acetate as catalyst.12 These fluorine-contain-
ing a,b-unsaturated ketones, which are electron-poor
1-oxa-1,3-butadienes, could be used in inverse electron
demand hetero Diels–Alder (HDA) reaction with elec-
tron-rich olefins to give tetrasubstituted dihydropyrans
in quantitative yields.
room temperature, and two products were isolated by
column chromatography as white solids (Table 1, entry
1).
On the basis of the spectral data, the byproduct was
determined as the dihydrofuran derivative 3a. For the
major product, its MS spectrum presented molecular
ion peak at m/z 506/508. The typical strong infrared
absorption of a,b-unsaturated ketone was appeared at
1
1671 cmꢀ1 in IR spectrum. Meanwhile, the H NMR
spectrum showed that it existed as one sole isomer. A
single peak of the proton linked to newly formed car-
bon–carbon double bond was at d 8.12 ppm. The chem-
ical shifts of other 10 aromatic protons were between d
7.28 and 7.95 ppm. Based on all of the spectral data, this
compound was easily identified as the expected conden-
sation product 4a. The E-type configuration of the car-
bon–carbon double bond was further confirmed by its
X-ray single-crystal diffraction analysis (Fig. 1).13
Initially, various amines (piperidine, DBU, triethyl-
amine) were employed to facilitate the model reaction
of 1a with excessive benzaldehyde 2a at room tempera-
ture for synthesis of the expected a-perfluoroalkane-
sulfonyl-a,b-unsaturated ketone. Although TLC
analysis showed that a small quantity of a,b-unsaturated
ketone was formed at the beginning, while it was gradu-
ally transformed to dihydrofuran derivative 3a in the
reaction process. This disappointing result could be
attributed to the amine’s basic property. It snatched a
proton from 1a, and the a,b-unsaturated ketone was
readily reacted with the formed anion to give 3a. To
weaken the basicity of the catalyst was, therefore, the
key to prevent the undesired Michael addition.
Further studies showed that reducing the catalyst load-
ing to 0.2 equiv would decrease the conversion of 1a and
the yield of 4a (Table 1, entry 2). Addition of molecular
sieves could promote the complete transformation of 1a
and improve the yield of 4a (Table 1, entry 3). Further-
more, several solvents were investigated. Benzene was
the best one for this reaction, other solvents, such as
CH3CN and THF, favored the formation of 2,3-
dihydrofuran derivative 3a. Under the established opti-
mized reaction conditions, a series of a-perfluoro-
alkanesulfonyl-a,b-unsaturated
ketones
4
were
synthesized from 1 with various aromatic aldehydes 2
After investigation, it was found that ammonium ace-
tate was a suitable catalyst for the Knoevenagel conden-
sation between 1a and benzaldehyde 2a (Table 1). The
reaction proceeded smoothly in anhydrous benzene at
in moderate to good yields (Table 2).
As shown in Table 2, cinnamaldehyde and furfural also
reacted with 1a to give the corresponding condensation
Table 1. Knoevenagel reaction between 1a and 2a catalyzed by ammonium acetate
O
O
O
O
RfSO2
Ph
CH3COONH4
Benzene, r.t
Cl(CF2)4O2S
Ph
PhCHO
Ph
+
+
Ph
Ph
Ph
SO2Rf
2a (1mmol)
1a (0.5mmol)
3a
4a
Entry
AcONH4 (equiv)
Time (h)
Yielda (%)
4a
3a
1b
2b
3c
1
0.2
1
24
24
12
74
67
86
9
5
5
a Isolated yield based on 1a.
b 1a could not be completely converted. The residual material was not recycled.
c
˚
0.2 g molecular sieves (4 A) was added.

C. Xing et al. / Tetrahedron Letters 47 (2006) 4951–4955
4953
O
RfSO2
H2O
R
ArCHO
2
Ar
4
1
-AcONH4
SO2Rf
AcONH4
H2O
H
O
1
Ph
H3N
H
H
COPh
RfO2S
N
-OAc
2
3
H
Ar
H
H
Ar
8
7
AcO-
Scheme 3. Proposed mechanisms of the reaction to prepare a-
perfluoroalkanesulfonyl-a,b-unsaturated ketones 4.
Figure 1. X-ray crystallography of 4a.
product in good yield under the same conditions (Table
2, entries 6 and 7). However, the reaction of aromatic
aldehyde bearing strong electron-attracting group, such
as p-nitrobenzaldehyde, with 1a preferably gave 2,3-
dihydrofuran derivatives. As for more active 1b, which
always afforded 2,3-dihydrofuran derivatives as major
products even reacted with nonactivated aldehyde.
While it reacted with furfural to afford the expected
product 4h only in 47% yield, along with tetrasubsti-
tuted 2,3-dihydrofuran in 29% yield (Table 2, entry 8).
All the products were obtained as (E)-isomers, which
were fully characterized by their spectral data. Under
the same conditions, aliphatic aldehydes reacted with 1
to give complex compounds, which were hard to be sep-
arated. Ketones did not react with 1.
trans conformation for the sake of stereohindrance.
Finally, the elimination of ammonia stereospecifically gave
the expected E-type condensation product 4 and regen-
erated ammonium acetate. As a neutral salt, ammonium
acetate could hardly seize the proton of 1 to form the
anion, thus holding back the subsequent Michael addi-
tion of 1 on a,b-unsaturated ketone 4. The addition of
molecular sieves removed the formed water from the
system, which obstructed the hydrolysis of 4 and then
insured the complete conversion of 1.
With a-perfluoroalkanesulfonyl-a,b-unsaturated ke-
tones 4 in hand, we investigated their cycloaddition with
diene or 1,3-dipole.14 To our surprise, 4a did not react
with 1,3-dimethyl-1,3-butadiene or 4-methoxy-benzonit-
rile-N-oxide at all. It could be attributed to the steric
hindrance of phenyl group at one-site of 4a.
According to the above results, a possible mechanism
for the reaction was proposed (Scheme 3). First, the aro-
matic aldehyde 2 was activated by ammonium acetate to
produce the strong electrophile iminium intermediate 7,
which accepted the nucleophilic attack of 1 to afford an-
other intermediate 8. The two large neighboring groups
at C-2 (RfSO2) and C-3 (Ar) of 8 preferably adopted
Recently, as a powerful method for the preparation of
polysubstituted dihydropyrans, the inverse electron de-
mand hetero Diels–Alder (HDA) reaction of oxabuta-
dienes with electron-rich olefins has attracted great
attentions.15 The cycloadduct dihydropyrans, and their
Table 2. Knoevenagel condensation reaction between 1 and aromatic aldehydes 2 catalyzed by ammonium acetate
O
O
RfSO2
CH3COONH4, 4ÅMS
R
RfO2S
ArCHO
+
R
Benzene, r.t.
Ar
1a R=Ph, Rf=Cl(CF2)4
1b R=CH3,Rf=Cl(CF2)4
1c R=Ph, Rf=CF3
2
4
Entry
1
Ar in 2
Time (h)
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
10
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
C6H5 (2a)
12
12
12
16
16
4
8
8
12
16
4a
4b
4c
4d
4e
4f
86
71
83
63b
51
78
94
47c
90
54
p-CH3OC6H4 (2b)
p-CH3C6H4 (2c)
p-BrC6H4 (2d)
o-BrC6H4 (2e)
C6H5CH=CH (2f)
2-furyl (2g)
2-furyl (2g)
C6H5 (2a)
p-BrC6H4 (2d)
4g
4h
4i
4j
a Isolated yield based on 1.
b This product could not be isolated from the excessive p-bromobenzaldehyde.
c Tetrasubstituted 2,3-dihydrofuran was also isolated in 29% yield.

4954
C. Xing et al. / Tetrahedron Letters 47 (2006) 4951–4955
derived tetrahydropyrans, are prevalent structural sub-
units in numerous important natural products.16 Due
to the strong electron-withdrawing ability of perflu-
oroalkanesulfonyl groups, a-perfluoroalkanesulfonyl-
a,b-unsaturated ketones 4 may act as one sort of elec-
tron-poor 1-oxa-1,3-butadienes to react with electron-
rich olefins.
two isomers’ anomeric protons. The relative configura-
tions of the isomers of 6c and 6e were also confirmed
1
by H–1H NOESY experiments.
In summary, we have established the stereospecific syn-
thesis of (E)-3-aryl-2-perfluoroalkanesulfonyl-1-phenyl-
prop-2-en-1-one from the condensation reaction
between b-keto perfluoroalkanesulfones and aromatic
aldehydes in the presence of ammonium acetate. These
We first tried the HDA reaction of 4g with excessive iso-
butyl vinyl ether 5a. To our delight, the cycloaddition
proceeded smoothly under solvent-free condition at
80 °C. The reaction was completed within 3 h, and the
product 6e was formed in nearly quantitative yield with
a mixture of cis- and trans-diastereomers in a ratio of
66:34 (Table 3, entry 5). The dihydropyran structure
was unambiguously established by related spectral data,
electron-poor
a-perfluoroalkanesulfonyl-a,b-unsatu-
rated ketones readily reacted with electron-rich olefins
such as vinyl ethers to afford the tetrasubstituted 3,4-
dihydro-2H-pyran derivatives in quantitative yields.
Further studies on the diastereoselective and enantiose-
lective tandem-sequence Knoevenagel–hetero-Diels–
Alder reaction of b-keto perfluoroalkanesulfones,
aldehydes, and electron-rich olefins are in progress.
1
including IR, MS, H, and 13C NMR. The relative con-
figuration of each isomer could be ascertained through
1H–1H NOESY experiment, as well as comparing the
coupling constant of the anomeric proton H-2 signal
in its 1H NMR. Consulting the studies of Collignon
et al.15e and Tietze et al.,15g the observation of an
NOE effect between the anomeric proton H-2 and the
ortho-proton H-50 of furan-2-yl or the relative greater
coupling constant of H-2 in minor component indicated
its 2,4-trans configuration; for the major component, the
absence of NOE effect or the smaller coupling constant
of the anomeric proton H-2 confirmed its 2,4-cis-
configuration.
Acknowledgment
This work was supported by the National Natural
Science Foundation of China (Nos. 20472106 and
20532040).
References and notes
1. Patai, S.; Rappoport, Z.; Stirling, C. The Chemistry of
Sulphones and Sulphoxides; John Wiley & Sons: New
York, 1988.
2. Simpkins, N. S. Sulphones in Organic Synthesis; Perg-
amon: Oxford, 1993.
3. Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. Y.
J. Org. Chem. 2003, 68, 1443.
4. Schank, K. Houben-Weyl, 4th ed.; Thieme: Stuttgart,
1985.
It was found that lowering the temperature or adding
other solvents would dramatically slow down the re-
action and suppress the conversion of 4g. Under the
established conditions (80 °C, solvent-free), other a-
perfluoroalkanesulfonyl-a,b-unsaturated ketones 4 also
reacted smoothly with vinyl ether to give the corre-
sponding dihydropyran derivatives 6 in quantitative
yields (Table 3).
5. (a) Stang, P. J.; Anderson, A. G. Inorg. Chem. 1976, 41,
781; (b) Stang, P. J.; Hanack, M.; Subramanian, L. R.
Synthesis 1982, 85.
All the products were diastereomeric mixtures. Some of
them could be separated by column chromatography.
The trans- or cis-configuration of each diastereomer
was established by comparing coupling constants of
6. (a) Hanack, M.; Bailer, G.; Hackenberg, J.; Subramanian,
L. R. Synthesis 1991, 1205; (b) Hendrickson, J. B.;
Bergeron, R.; Giga, A.; Sternbach, D. J. Am. Chem.
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Wareing, J. J. Am. Chem. Soc. 1974, 96, 2275; (d)
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Hendrickson, J. B.; Sternbarch, D. D.; Bair, K. W. Acc.
Chem. Res. 1977, 10, 306.
Table 3. HDA reaction of 4 with vinyl ether 5
O
Ar
RfSO2
O
RfSO2
Ph
80oC
neat
4
Ph
R'
5
6
3
2
+
1
Ar
O
OR'
7. Trost, B. M.; Ghadiri, M. R. J. Am. Chem. Soc. 1984, 106,
7260.
5a R'=Bui
5b R'=Et
6
4
8. (a) Bartlett, P. A.; Green, F. R., III; Rose, E. H. J. Am.
Chem. Soc. 1978, 100, 4852; (b) Mandai, T.; Yanagi, T.;
Araki, K.; Morisaki, Y.; Kawada, M.; Otera, J. J. Am.
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Taniguchi, T.; Tokunaga, Y.; Fukumoto, K. Tetrahedron
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Crouch, N. P.; Hill, R. L.; Laffey, T. G. Tetrahedron Lett.
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Tetrahedron: Asymmetry 1998, 9, 2311; (f) Marco, J. L.
J. Org. Chem. 1997, 62, 6575; (g) Swenson, R. E.; Sowin,
T. J.; Zhang, H. Q. J. Org. Chem. 2002, 67, 9182.
9. (a) Menke, O.; Steinhuber, E.; Martinez, A. G.; Subra-
manian, L. R.; Hanack, M. Synthesis 1994, 1291; (b)
Entry
4
5
Time (h) Product Yielda (%) cis:transb
1
2
3
4
5
6
7
4a 5a
4b 5a
4c 5b
4f 5a
4g 5a
4g 5b
5
5
5
3
3
3
4
6a
6b
6c
6d
6e
6f
98
99
97
96
96
97
97
58:42
66:34c
53:47c
54:46
66:34
64:36
53:47
4i
5b
6g
a Isolated yield based on 4.
b Determined by 1H NMR.
c The trans- and cis-diastereomeric mixtures could not be separated.

C. Xing et al. / Tetrahedron Letters 47 (2006) 4951–4955
4955
Goumont, R.; Magder, K.; Tordeux, M.; Marrot, J.;
Terrier, F.; Wakselman, C. Eur. J. Org. Chem. 1999,
2969.
mmꢀ1; h/2h scan mode 1.80°–26.00°; F(000) = 1016;
reflections collected/unique: 11091/4129 (Rint = 0.0546);
I > 2r(I) = 2801; parameter = 289; goodness of fit: 1.075;
final R indices [I > 2r(I)], R1 = 0.0827, wR2 = 0.2568; R
indices (all data), R1 = 0.1042, wR2 = 0.2826.
10. Xing, C. H.; Zhu, S. Z. J. Org. Chem. 2004, 69, 6486.
11. (a) Patent, Minnesota Min. Man.Co. US 3933914, 1976;
(b) Patent, Minnesota Min. Man.and Manyf. US 4018810,
1975.
14. No similar reactions about a-sulfonyl-a,b-unsaturated
ketones are reported to date.
12. Some examples of the Knoevenagel reaction on nonfluo-
rinated b-keto sulfones: (a) Ouvry, G.; Zard, S. Z.
Synlett 2003, 11, 1627; (b) Toutchkine, A.; Kraynov, V.;
Hahn, K. J. Am. Chem. Soc. 2003, 125, 4132; (c) Chodroff,
S.; Whitmore, W. F. J. Am. Chem. Soc. 1950, 15, 1073; (d)
Beck, G.; Guenther, D. Chem. Ber. 1973, 106, 2758; (e)
Naidu, M. S. R.; Naidu, R. R. Indian J. Chem. Sect. B
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15. (a) Arimori, S.; Kouno, R.; Okauchi, T.; Minami, T.
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Jacobsen, E. N. Angew. Chem., Int. Ed. 2002, 41, 3059; (d)
Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem.
Soc. 2000, 122, 1635; (e) Badri, H. A.; Maddaluno, J.;
Masson, S.; Collignon, N. J. Chem. Soc., Perkin Trans. 1
1999, 2255; (f) Weichert, A.; Hoffmann, H. M. R. J. Org.
Chem. 1991, 56, 4098; (g) Tietze, L. F.; Meier, H.; Nutt, H.
Chem. Ber. 1989, 122, 643.
13. Crystal data for compound 4a (CCDC No.: CCDC 293269):
C19H11F8O3ClS, MW = 506.79; monoclinic, P2[1]/n;
˚
˚
˚
a = 12.281 (10) A, b = 8.305(7) A, c = 20.906(17) A;
16. (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995,
117, 8126; (b) Kobayashi, M.; Aoki, S.; Kitigawa, I.
Tetrahedron Lett. 1994, 35, 1243.
3
˚
a = 90°, b = 100.13(10)°, c = 90°; V = 2099.2(3) A ; T =
293(2) K; Z = 4, Dc = 1.604 Mg mꢀ3; l (Mo Ka) = 0.371